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GartnerAnton

Gartner, Anton
DNA Damage Response and Genetic Toxicology
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A Role for the Nonsense-Mediated mRNA Decay Pathway in Maintaining Genome Stability in Caenorhabditis elegans

Author(s)
Gonzalez-Huici, VictorWang, BinGartner, Anton
Issued Date
2017-08
DOI
10.1534/genetics.117.203414
URI
https://scholarworks.unist.ac.kr/handle/201301/27441
Fulltext
https://www.genetics.org/content/206/4/1853
Citation
GENETICS, v.206, no.4, pp.1853 - 1864
Abstract
Ionizing radiation (IR) is commonly used in cancer therapy and is a main source of DNA double-strand breaks (DSBs), one of the most toxic forms of DNA damage. We have used Caenorhabditis elegans as an invertebrate model to identify novel factors required for repair of DNA damage inflicted by IR. We have performed an unbiased genetic screen, finding that smg-1 mutations confer strong hyper-sensitivity to IR. SMG-1 is a phosphoinositide-3 kinase (PI3K) involved in mediating nonsense-mediated mRNA decay (NMD) of transcripts containing premature stop codons and related to the ATM and ATR kinases which are at the apex of DNA damage signaling pathways. Hyper-sensitivity to IR also occurs when other genes mediating NMD are mutated. The hyper-sensitivity to bleomycin, a drug known to induce DSBs, further supports that NMD pathway mutants are defective in DSB repair. Hyper-sensitivity was not observed upon treatment with alkylating agents or UV irradiation. We show that SMG-1 mainly acts in mitotically dividing germ cells, and during late embryonic and larval development. Based on epistasis experiments, SMG-1 does not appear to act in any of the three major pathways known to mend DNA DSBs, namely homologous recombination (HR), nonhomologous end-joining (NHEJ), and microhomology-mediated end-joining (MMEJ). We speculate that SMG-1 kinase activity could be activated following DNA damage to phosphorylate specific DNA repair proteins and/or that NMD inactivation may lead to aberrant mRNAs leading to synthesis of malfunctioning DNA repair proteins.
Publisher
GENETICS SOCIETY AMERICA
ISSN
0016-6731
Keyword (Author)
ionizing radiationdouble-strand-break repairnonsense-mediated mRNA decaytranscription-replication interfacemitosis
Keyword
DOUBLE-STRAND BREAKDNA-DAMAGE RESPONSEMAMMALIAN-CELLSHOMOLOGOUS-RECOMBINATIONGENE-EXPRESSIONSTRESS-RESPONSEC-ELEGANSREPAIRDEGRADATIONMECHANISMS

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